Novel Protein Biomarkers of Corticolimbic Pathophysiology in Lewy body Dementia

路易体痴呆皮质边缘病理生理学的新型蛋白质生物标志物

基本信息

批准号：
10514142
负责人：
ALLAN I LEVEY
金额：
$ 164.1万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10514142
关键词：
Address Alzheimer&apos s Disease Amygdaloid structure Anti-Anxiety Agents Antipsychotic Agents Automobile Driving Autopsy Base of the Brain Biological Assay Biological Markers Blood Blood Vessels Brain Brain region Caregivers Cerebrospinal Fluid Cholinesterase Inhibitors Clinical Cognitive Collection DNA Data Delusions Dementia with Lewy Bodies Detection Deterioration Diagnostic Disease Distress Early Diagnosis Emotional Disturbance Endothelium Enrollment Fostering Functional disorder Future Health Care Costs Immune Immunologics Individual Knowledge Lewy Body Dementia Lewy Body Disease Link Longitudinal cohort Mass Spectrum Analysis Measures Mediating Medicine Memory Metabolism Methods Molecular Profiling Monitor Nerve Degeneration Network-based Neurodegenerative Disorders Neurons Paranoia Parkinson Disease Parkinson&apos s Dementia Pathway Analysis Pathway interactions Patients Pharmacotherapy Phenotype Plasma Progressive Disease Proteins Proteome Proteomics RNA Regional Disease Registries Research Sampling Schedule Source Specificity Synapses Techniques Temporal Lobe Therapeutic Thinking Tissues Translating Validation Visual Hallucination Whole Blood aptamer base biobank biomarker discovery biomarker panel biomarker validation candidate marker cohort effective therapy experience experimental study frontal lobe innovation multidisciplinary myelination neuropsychiatry novel novel marker personalized care personalized therapeutic phenotypic data programs promoter protein biomarkers recruit risk stratification synuclein synucleinopathy targeted biomarker therapeutic biomarker treatment response validation studies

项目摘要

Project Summary Lewy body dementia (LBD), a class of disorders comprising Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), features aggressive cognitive and neuropsychiatric decline without cure or effective mitigating therapies. Driving the clinical challenges surrounding LBD is a poor understanding of the pathophysiology underlying its clinical deterioration and a desperate lack of diagnostic, progressive, and therapeutic biomarkers. Neuropathological evidence suggests that corticolimbic synucleinopathy is closely linked to the aggressive dementia of LBD and that effective biomarkers of cognitive and neuropsychiatric decline would necessarily reflect this corticolimbic dysfunction. Thus, our central hypothesis is that the corticolimbic LBD brain features regional and disease-specific alterations in neuronal and non-neuronal pathways reflected as unique protein signatures in CSF and plasma. To investigate this hypothesis, we will apply an integrated network-based proteomic pipeline across brain, cerebrospinal fluid (CSF), and plasma to identify LBD biofluid signatures anchored in corticolimbic pathophysiology. Our preliminary experience with this pipeline suggests it is a powerful promoter of multiplexed biomarker assays reflective of diverse brain-based dysfunction, including neuronal, glial, and endothelial pathophysiology. In addition to these proteomic experiments, we will also establish an Emory LBD registry under the Parkinson’s Disease Biomarker Program (PDBP) and utilize its clinical and biospecimen data to fuel proteomic validation studies and promote future LBD research. Our specific aims include 1) building a longitudinal PDBP registry for LBD, 2) defining the corticolimbic network proteome of LBD, 3) performing brain-biofluid proteomic integration to identify promising biofluid markers, and 4) longitudinal biofluid validation using targeted proteomic strategies. In addition to biospecimens collected in Aim 1, we will supplement these experiments using existing brain and biofluid samples housed in Emory Goizueta Alzheimer’s Disease Research Center biorepositories. Ultimately, our efforts to identify molecular signatures of cognitive and neuropsychiatric decline in LBD promise to discover novel biomarkers to enhance early diagnosis, disease monitoring, and gauging therapeutic response. Furthermore, such markers can serve as a necessary gateway to effective drug therapies for this devastating spectrum of neurodegenerative diseases.

项目概要路易体痴呆 (LBD)，一类疾病，包括帕金森病痴呆 (PDD) 和痴呆路易体 (DLB)，具有侵袭性认知和神经精神下降，无法治愈或有效缓解 LBD 相关临床挑战的原因是对 LBD 的了解不足。其临床恶化和极度缺乏诊断、进展和治疗的病理生理学基础治疗性生物标志物表明皮质边缘突触核蛋白病密切相关。与 LBD 的侵袭性痴呆有关，并且认知和神经精神下降的有效生物标志物将因此，我们的中心假设是皮质边缘LBD。大脑特征反映了神经元和非神经元通路的区域和疾病特异性改变作为脑脊液和血浆中独特的蛋白质特征为了研究这一假设，我们将应用综合方法。基于网络的跨大脑、脑脊液 (CSF) 和血浆的蛋白质组管道，用于识别 LBD 生物流体我们对该管道的初步经验表明了这一点。是反映多种脑功能障碍的多重生物标志物检测的强大促进剂，包括除了这些蛋白质组学实验之外，我们还将进行神经元、神经胶质和内皮病理生理学。根据帕金森病生物标志物计划 (PDBP) 建立埃默里 LBD 登记处，并利用其临床和生物样本数据，以促进蛋白质组学验证研究并促进未来的 LBD 研究。包括 1) 建立 LBD 的纵向 PDBP 注册表，2) 定义 LBD 的皮质边缘网络蛋白质组， 3) 进行脑-生物体液蛋白质组整合，以确定有前途的生物体液标记物，以及 4) 纵向使用目标蛋白质组学策略进行生物流体验证除了目标 1 中收集的生物样本外，我们还将收集生物样本。使用埃默里戈伊苏埃塔阿尔茨海默病中心现有的大脑和生物流体样本来补充这些实验最终，我们努力识别认知和疾病的分子特征。 LBD 的神经精神衰退有望发现新的生物标志物，以增强疾病的早期诊断此外，此类标记物可以作为必要的门户。针对这种毁灭性的神经退行性疾病的有效药物疗法。